肿瘤细胞治疗研究
英文原题：HMGB1 ubiquitination inhibition and extracellular secretion, mediated by m(6)A modified-exosomal lncRNA MALAT1, creates a communication between NK92-MI cells and tumor cells to aggravate acute lymphoblastic leukemia.
ALL细胞来源的外泌体MALAT1受METTL14介导的m6A修饰上调，随后在NK92-MI细胞中抑制HMGB1泛素化和降解，导致ALL细胞对阿霉素耐药和恶性生长。因此，抑制METTL14/MALAT1/HMGB1轴可能是ALL患者的治疗策略。
MALAT1已被证实促进急性淋巴细胞白血病（ALL）的进展，但其具体机制仍不清楚。本研究探讨了ALL细胞来源的外泌体MALAT1在ALL细胞化疗耐药和恶性生长中的功能作用及其潜在机制。
采用qRT-PCR、Western blotting、免疫荧光和免疫组化染色评估靶分子的表达。采用CCK-8、EdU染色和流式细胞术检测细胞增殖和凋亡。采用RIP、RNA-pull down、Co-IP和MeRIP探究分子机制。将ALL细胞注射入裸鼠以评估体内成瘤能力。
MALAT1 和甲基转移酶样 14（METTL14）在 ALL 中上调，且呈正相关。METTL14 介导的 m6A 修饰提高了 MALAT1 的稳定性和表达，进而促进 ALL 细胞生长并抑制凋亡。此外，MALAT1 通过 hnRNPA2B1 被包装进 ALL 细胞来源的外泌体，随后转移至 NK92-MI 细胞。外泌体 MALAT1 抑制了 NK92-MI 细胞中含三方基序蛋白 27（TRIM27）介导的高迁移率族蛋白 B1（HMGB1）泛素化，从而导致 ALL 细胞对阿霉素耐药及恶性进展。
BACKGROUND: MALAT1 has been validated to favor the progression of acute lymphoblastic leukemia (ALL), but its detailed mechanism remains obscure. This study explored the functional roles of ALL cells-derived exosomal MALAT1 in chemoresistance and malignant growth of ALL cells, as well as its underlying mechanisms. METHODS: The expression of target molecules was evaluated by qRT-PCR, Western blotting, immunofluorescence, and immunohistochemical staining. CCK-8, EdU staining and flow cytometry were conducted to determine cell proliferation and apoptosis. RIP, RNA-pull down, Co-IP, and MeRIP were used to investigate molecular mechanisms. ALL cells were injected into nude mice to evaluate in vivo tumor formation. RESULTS: MALAT1 and methyltransferase-like 14 (METTL14) were up-regulated in ALL, which exhibited a positive correlation. METTL14-mediated m 6 A modification raised MALAT1 stability and expression, and consequently facilitated ALL cell growth and apoptosis inhibition. Furthermore, MALAT1 was packaged into ALL cells-derived exosomes by hnRNPA2B1, and then transferred to NK92-MI cells. Exosomal MALAT1 suppressed tripartite motif-containing 27 (TRIM27)-mediated ubiquitination of High-mobility group box 1 (HMGB1) in NK92-MI cells, thereby leading to adriamycin resistance and malignant development of ALL cells. CONCLUSION: ALL cells-derived exosomal MALAT1 was up-regulated by METTL14-mediated m 6 A modification, and subsequently restrained HMGB1 ubiquitination and degradation in NK92-MI cells, which resulted in adriamycin resistance and malignant growth of ALL cells. Therefore, inhibition of METTL14/MALAT1/HMGB1 axis might be a therapeutic strategy for ALL patients. HIGHLIGHTS: (1) METTL14 and MALAT1 were positively correlated in ALL samples. (2) METTL14 increased MALAT1 stability and expression in an IGF2BP1-mediated m6A manner. (3) ALL cells transferring exosomal MALAT1 suppressed TRIM27-mediated HMGB1 ubiquitination in NK92-MI cells. (4) HMGB1 silencing in NK92-MI cells enhanced adriamycin sensitivity of ALL cells. (5) MALAT1/HMGB1 axis inhibition delayed in vivo ALL growth via NK cell activation.
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